PT99132A - METHOD FOR THE PREPARATION OF 4-OR SUBSTITUTED PYRIDINE-2-CARBOXYLIC ACID AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

Description of the invention patent of HOECHST AKTIENGE-SELLSCHAFT, German, industrial and commercial, headquartered at D-6230 Frankfurt am Main 80, Federal Republic of Germany, (inventors: Dr. Ekkehard Baader, Dr. Martin Bickel, Dr. Volkmar Gunzler -Pukall and Dr. Manfred Volkz, residing in the Federal Republic of Germany, for " PROCESS FOR THE PREPARATION OF PYRID-2-CARBOXYLIC ACID SUBSTITUTES IN POSITION 4 OR 5 AND OF PHARMACEUTICAL COMPOSITIONS CONTAINING THEM "

DESCRIPTION

Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing the specific hydroxylation reactions of collagen. In the course of these reactions, the hydroxylation of proline or lysine, bound by protein, occurs through the enzymes proline hydroxylase or lysine hydroxylase. If this restriction is limited by inhibitors, then a subhydroxylated collagen molecule is formed, incapable of performing its functions, which can only be produced by the cells in the extracellular space in small quantity. The collagen sub-hydroxy side, moreover, can not be incorporated into the collagen matrix and is proteolytically decomposed very easily. As a consequence of these effects, the total amount of extracellularly deposited collagen is reduced. It is known that the inhibition of proline hydroxylase by known inhibitors, such as p-tocopherol

, < x '-dipyridyl, lead to an inhibition of Clq biosynthesis and macrophages (W.Muller et al., FEBS, 90 (1987), 218, Immunology 155 (1978), 47). In this way, the classical path of complementary activation ceases to take place. The inhibitors of rolinahydroxylase therefore also act as immunosuppressants, for example in diseases of the immune complex. It is known that the enzyme prohydroxylates is effectively inhibited by pyridine-2,4-dicarboxylic acids and pyridine-2,5-dicarboxylic acids (K. Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). Such compounds, however, are only effective as inhibitors when in very high concentrations in the cell culture (Tschank, G. et al., Biochem, J. 248 (1987) 625-633).

In DE A 34 32 094 the disclosures of pyridine-2,4-dicarboxylic and pyridine-2,5-dicarboxylic acids having 1 to 6 atoms in the alkyl group of the ester are described as medicaments for inhibition of proline hydroxylase and lysine hydroxylase.

Such lower alkyl diesters, however, have the disadvantage of being decomposed too rapidly to acids in the body and not reaching their site of action in the cell in sufficiently high concentration, and are thus less suitable for possible prescription as pharmaceuticals. DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 generally disclose mixed esters / amides, higher alkyl diesters and diamides of pyridine-2,4-dicarboxylic acids and pyridine- 2,5-dicarboxylic acids, which effectively inhibit collagen biosynthesis in the animal model. Thus, DE-A 37 03 959 discloses, among others, the description of the synthesis of N, N 1 -bis (2-methoxy-ethyl) -pyridine-2,4-dicarboxylic acid diamide and N, N'-bis (3-isopropoxypropyl) pyridine-2,4-dicarboxylic acid.

In the German patent applications P 38 26 471.4 and P 38 28 140.6 an improved process is suggested

V erotized for the preparation of N, N'-bis (2-methoxy-ethyl) -pyridine-2,4-dicarboxylic acid diamide. German patent application P 39 24 093.2 suggests new diamines of N, N'-bis (alkoxy-alkyl) -pyridine-2,4-dicarboxylic acid. German patent application P 40 01 002.3 discloses the use of pyridine-2,4-dicarboxylic acid di (nitroxyalkyl) diamides and pyridine-2,5-dicarboxylic acid for the preparation of proline hydroxylase inhibitor and lysine hydroxylase inhibitors.

Both the pyridino-2,4-dicarboxylic acid and pyridine-2,5-dicarboxylic acid diamides are known as auxiliary agents for fighting tuberculosis (Hirakata et al., J. Pharma. Soc., Japan 77 (1957) 219 and Haring et al. al., Helv. 37 (1954) 147, 153) as well as the dihydrazides of pyridine-2,4-dicarboxylic acid and pyridine-2,5-dicarboxylic acid (Itai et al., Biol. 1956), 115, 117 and Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839).

JP 53/28175) (78/28175) describes N, N'-bis (2-nitroxyethyl) pyridine-2,4-dicarboxylic acid and N, N'-bis (2-nitroxyethyl) pyridine-2 , 5-dicarboxylic acid, as a substance having a vasodilatory effect. German Patent Application (H0E 90 / F192) describes the use of pyridine-N-oxides with substituents at the 2,4 and 2,5 positions for the preparation of proline hydroxylase and lysine hydroxylase inhibitor drugs.

Surprisingly it has now been found that 4-or 5-substituted pyridine-2-carboxylic acids of the general formula I below, as well as their physiologically acceptable salts, effectively inhibit lysine hydroxylase and proline hydroxylase in the animal model.

Accordingly, in accordance with the present invention, the compounds of claim 3,

according to the formula I R 2 R 2 N (O) C

COOH (I) in which n is 1 and 2, and R 2, independently of one another, are hydrogen, C 1-12 -alkoxy, C 2 -C 12 -alkenyl; C1 -C4 -cycloalkyl, whether or not fused to the benzene, aryl or heteroaryl ring, these radicals being mentioned for R3 and R4 are unsubstituted or substituted R5 the same or different 1,2 or one or more radicals such as halogen, hydroxy, cyano, nitro, nitroxy, amino, carboxyl, C1 -C4 -alkoxy, C1 -C4 -alkoxycarbonyl, C1 -C4 -alkylamino or di- (C1 -C4) C1-4 alkylamino, indolyl or phenyl, such that the indolyl radical and the phenyl radical are either unsubstituted or substituted by halogen, nitro, C1 -C4 -alkyl] alkoxy, such that in the case of substitutions or C 1 -C 4 -alkoxy, such multiple, the radicals are the same or different from each other, or

R represents hydrogen, represents from which radical -N (R 2) (R 2) > in which R5 and R5 are the same or different and represent hydrogen, C1 -C4 -alkyl, C1 -C4 -alkylcarbonyl or phenyl, R1 and R2 are the same or different from each other and represent hydrogen, C1-C4-alkyl, C1 -C4 -alkylcarbonyl or phenyl, a

, Wherein R represents an amino acid, an amino acid ester, an amino acid amide, an amino acid alkylamide or dialkylamide, said alkyl radicals being 1 up to 4 carbon atoms and may optionally be monosubstituted by phenyl, and such that the C1-4 alkyl and C1-4 alkyl radicals may also be branched, the amino acid radical being attached through a terminal nitrogen atom, or wherein R 1 represents hydrogen, represents a radical, attached through an N-terminus, of dipeptide or tripeptide, wherein, as " radical " is meant the corresponding? -α-amino acid and its derivatives or the dipeptide or tripeptide, always bound by the N-terminus, and

2 has the meaning of R 2, such that the radicals R 2 and R 2 are the same or different from each other, or R 2, together with the nitrogen atom to which they are attached;

(CH2) 2 'n wherein n is 1 to 3 and is 0, S, CH2 or hydrogen, -N (R6) -, phenyl, such that C 1 -C 18 alkyl >

W 5

-alkenyl or C 2 -C 4 -alkynyl such that these radicals are either unsubstituted or substituted by phenyl, which in turn either is unsubstituted or has one or more substitutions by one or more identical or different substituents, R3 is selected from the group consisting of: halogen, nitro, cyano, carboxy, hydroxy, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or wherein R7 represents hydrogen or C1 -C4 alkyl, alkyl, or -CONR7 or -CONR8) 9 or CONHR6, wherein R7 has the meaning of R1, or (R3) represents a C1 -C4 -alkylene chain in which there has been no group or of a C1-4 group not directly adjacent to the nitrogen atom by O, S or N-R7, or such that R6 is C1 -C4 -alkoxycarbonyl or C1 -C7 -cycloalkyl, as well as the physiologically The amides at positions 4 and 5 of pyridine-2-carboxylic acid (4 or 5) -carboxylic acids are excluded.

The compounds of formula I in which R 1 and R 2 are each independently of the other represent hydrogen, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, aryl or heteroaryl radicals such that these radicals are unsubstituted or substituted by one or two radicals R, which are the same or different from each other, R 2 represents halogen, hydroxy, cyano, amino, carboxy,

C1 -C4 -alkylamino or di- (C1 -C4) -alkylamino or phenyl, wherein the phenyl radical is either unsubstituted or substituted by halogen, C1 -C2 -alkyl or C1 -C2 -alkoxy , 6

or where R 1 represents hydrogen, represents a radical -N (R 2) (R 2), in which R 1 and R 2 are the same or different from each other and represent hydrogen or alkyl, or provided that R 1 represents hydrogen, represents a radical , linked through the N-terminus, of an amino acid, or of an alkyl ester of < 4-amino acid, wherein the alkyl radical has 1 to 3 carbon atoms and is optionally monosubstituted by phenyl and wherein the C1-4alkyl radical may also be branched, and 211 has the meaning of R3, the radicals R1 and R2 being the same or different from each other or 2

R 2 together with the nitrogen atom to which they are attached form a radical of formula II

N is 1 to 3 and represents O, Cl, or -N (R) -, in which R represents hydrogen, phenyl, C 1 -C 4 -alkyl such that these radicals are mentioned or do not have substitution or are substituted by C -C-C--alkoxycarbonyl or C -C-C ciclo-cycloalkyl, as well as the physiologically acceptable salts, the 4- (5-pyridino-2- carboxylic acid. Particular preference is given to compounds of general formula I in which R 1 and R 2, independently of one another, represent hydrogen, C 1 -C 6 -alkyl, especially C 1 -C 4 -alkyl, C 1 -cycloalkyl, phenyl or pyridyl, wherein these radicals cited for R 2 and R 5 are either unsubstituted or substituted by one or two radicals R 1 or 2 identical or different from each other, such that R 3 represents hydroxy, amino, carboxy, C1 -C4 -alkoxy, especially methoxy, C1 -C4 -alkoxycarbonyl or phenyl, wherein the phenyl radical is either unsubstituted or has a single substitution by methyl or methoxy and R 2 and R 2 being the same or different from each other or

R 2 and R 3 together with the nitrogen atom to which they are attached form a radical of formula II in which n is 2 and A represents O or C 1 - as well as the physiologically acceptable salts thereof, the pyridine-2-carboxylic acid (4 or 5) -carboxylic acid 4- or 5-amides being excluded.

The compounds mentioned as being excluded, 4- or 5-amides of pyridine-2-carboxylic acid - (4 or 5) -carboxylic acid have already been described as such in Thums, 8 L. J.Pharm

and Delarge,

Belg. 24 (1-2), 3-21 (1969) J. Pharm.

Minutes. Helv 44 (10), 637-43 (1969).

Halogens are fluoro, chloro, bromo and iodo, such as aryl, phenyl and naphthyl, and as heteroaryl, 5- and 6-membered aryl radicals containing 1, 2 or 3 nitrogen atoms and / or oxygen and / or sulfur, which may also optionally be condensed to the benzene ring; in the case of the heteroaryl radicals, are in particular pridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3,5-triazyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, oxazolyl and thiazolyl radicals, and optionally their radicals. compounds condensed with a benzene ring.

Where multiple substitutions are meant, it is meant in the foregoing and in the following that at least 2 and at most all of the hydrogen atoms present on the alkyl radicals are exchanged for the said substituents. Preferably, there is in this case one substituent for each methyl or methylene group.

In the case of polysubstitutions the substituents may also be independent of one another.

In addition, the invention relates to the use of the compounds of general formula I, as well as their physiologically acceptable salts, including pyridine-2-carboxylic acid (4,5) -carboxylic acid 4- , for the preparation of a proline hydroxylase and lysine hydroxylase inhibitor.

Finally, the invention relates to compounds of general formula I, including pyridine-2-carboxylic acid (4 or 5) -carboxylic acid 4- or 5-amides for use as medicaments.

In particular the invention relates to compounds of formula I, including the aforementioned amides, for application as fibrosuppressants and immunosuppressants, as well as for the inhibition of proline hydroxylase and lysine.

'> droxylase and to influence the metabolism of collagen and collagen-like substances or Clq biosynthesis.

All quoted alkyl radicals containing more than two carbon atoms may be either straight chain or branched chain.

Further the invention relates to a process for the preparation of compounds of general formula I, including pyridine-2-carboxylic acid (4 or 5) -carboxylic acid 4- or 5-amides. The process according to the invention is hereinafter elucidated based on the example of pyridine-2,4-dicarboxylic acid. The process for compounds according to the invention with substitution 2,5 occurs in an analogous manner.

- 10 -

Reaction scheme

Step 5:

V (III) C0NR1R2 iC02CH3 6

C02H11 (I ')

the conversion of the commercially available pyridine-2,5-dicarboxylic acid into the corresponding dicarboxylic acid dihalide, preferably in the dichloride, and the conversion of the dihalide into the pyridine-2,4-dicarboxylic acid dibenzyl ester, for example by reaction with an optionally substituted benzyl alcohol.

According to step 2, the selective saponification at the 2-position of the diester is carried out, for example in the presence of a copper catalyst, according to Delarge, J .: Phar. Acta.Helv. 44 (10), 637 (1969). The free acid function at the 2-position is then converted in step 3 to the corresponding acid chloride, the reaction is carried out with an alcohol, such as methyl alcohol or ethyl alcohol, with formation of the corresponding 2-carboxylic ester. The benzyl blocking group remaining at the 4-position and, according to step 4, hydrolygenetically separated (for example with 1% Pd, Houben-Weyl: volume IV / 1c (1980), pages 381-382) and free acid at the 4-position is transformed into the corresponding acid chloride. The acid chloride may now react with the amine of formula III, in which R and R have the meanings as in the compounds of formula I, with the formation of the combined pyridine-4-carboxamide-2-carboxylates . The carboxylic acid ester in the 1-position can now, in conclusion, (step 6) be reacted with an alkali metal hydroxide in alcoholic solution (for example sodium hydroxide in ethanol), the salt of carboxylic acid, which is then converted into the corresponding compound of formula I by reaction with mineral acids (such as, for example, hydrochloric acid). The title compound was prepared according to the same procedure as described above.

substituted in the 4-position, also applies to the compounds which are correspondingly substituted in the 5-position.

Compounds of formula I, including pyridine-2-carboxylic acid (4 or 5) -carboxylic acid 4- or 5-amides, have valuable pharmacological properties and show in particular effectiveness as inhibitors of proline hydroxylase and lysine hydroxylase, as fibrosuppressive agents and as immunosuppressants. Fibrogenase activity can be determined by radioimmunoassay of the N-terminal propeptide of collagen type III or the N-terminal or C-terminal cross-linking domains of collagen-neo-type-IV (collagen-7s collagen or NC type IV). deo of a) b)

To this end, the concentrations of hydroxyproline, procollagen-III-petin, collagen and collagen-type IV-Ig in the liver were treated with untreated guinea pigs (control) guinea pigs which were treated with carbon tetrachloride (c) guinea pigs, which were initially treated with CCl 3 and then with the compound according to the invention (this test method is described by Rouiller, C., experimental toxic injury of the liver; in The Liver, C. Rouiller, vol.2, pages 335-476, New York, Academic Press, 1964).

The compounds of formula I, including pyridine-2,4-dicarboxylic acid 4-amide and pyridine-2,5-dicarboxylic acid 5-amide, can be used as medicaments in the form of pharmaceutical compositions which contain such optionally together with compatible pharmaceutical carriers. The compounds may find use as curative agents, for example in the form of pharmaceutical preparations, which contain such compounds in admixture with an organic or inorganic pharmaceutical carrier suitable for enteral, percutaneous or parenteral application,

such as water, gum arabica, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, and the like.

To this end, they may be administered orally at doses of 0.01-25.0 mg / kg / day, preferably 0.01-5.0 mg / kg / day, or parenterally at doses of 0.001-5 mg / kg / day, preferably 0.001 - 2.5 mg / kg / day, especially 0.005 - 1.0 mg / kg / day. The dosage can also be increased in difficult cases. In many cases, however, smaller doses are also sufficient. These data relate to an adult of about 75 kg. The further object of the invention are medicaments which contain one or more compounds of formula I according to the invention and / or their physiologically acceptable salts, including pyridine-2-carboxylic acid 4- or 5-amides ( 4 or 5) -carboxylic acid.

The medicaments are prepared by processes known in principle, common to the person skilled in the art. As medicaments, the physiologically active compounds (= active substance) according to the invention are employed either as such or preferably in combination with suitable auxiliary or carrier pharmaceutical substances in the form of tablets, pills, capsules, suppositories, emulsions , suspensions or solutions, the active substance content being up to about 95% advantageously between 10 and 75%.

Suitable auxiliary or carrier substances for the desired drug formulation are, for example, along with solvents, gel formers, suppository bases, tablet aids and other active substance carriers, as well as antioxidants, dispersing agents, emulsifiers , antifoams, flavoring agents, preservatives, solubility promoters or dyes.

The active substances may be applied orally, parenterally or rectally. 14

The active compounds are mixed with the appropriate additives such as carriers. stabilizers or inert diluents and transformed into suitable prescription forms by the usual methods, such as tablets, dragees, suppositories, aqueous suspensions! alcoholic or oily substances, or aqueous or oily solutions.

As inert carriers may be used for example gum arabic, magnesia, magnesium carbonate, post-phosphate, lactose, glucose or starches, especially corn starch. The preparation can be made either in the form of dry granules or wet granules. Suitable carriers or oily solvents are: for example vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous application, the active compounds are transformed if desired in solution, suspension or emulsion, with suitable suitable substances such as solubility promoters, emulsifiers or other auxiliary substances. Suitable solvents are, for example, saline or alcohols, for example ethanol, propanol, glycerin, and in parallel also solutions of sugars such as glucose or mannitol solutions, or also a mixture of the different solvents mentioned. The invention is further elucidated by examples.

Example 1 Pyridine-2,4-dicarboxylic acid dibenzyl ester (step 1) and 30 g of pyridine-2,4-dicarboxylic acid are converted into the acid chloride with 30 ml of thionyl chloride and reacted with 43, 8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether.

Yield: 42.1 g Melting point 63-65 ° C

Example 2 Pyridine-2,4-dicarboxylic acid 4-benzyl ester (step 2)

40 g of pyridine-2,4-dicarboxylic acid dibenzyl ester of Example 1 are added to a suspension of 27.8 g of copper nitrate II in 700 ml of methanol. Boil for one hour under reflux, and the copper complex is removed by filtration after cooling. The complex is suspended in dioxane and hydrogen sulphide is introduced into the suspension. The precipitated copper sulphide is removed by filtration and the organic phase is concentrated. The product is mixed by stirring with petroleum ether.

Melting point 113-115 ° C

Yield: 25.3 g Example 3 4-Benzyl, 2-methyl ester of pyridine-2,4-carboxylic acid (step 3) 34 g of the compound of example 2 are placed in 11 of tetrahydrofuran. Cool to 0 ° C and at this temperature, 250 ml of a diazomethane solution are slowly added dropwise to this solution. Allow the temperature to drop to room temperature and stir for 12 hours. The solution is concentrated and chromatographed on the crude product (silica gel, ethyl acetate as eluent.

Melting point: 58 C

Yield: 26 g

Example 4 Pyridine-2,4-dicarboxylic acid 2-methyl ester (step 4) At room temperature, the compound of Example 3 is dissolved in 1 L of dioxane. 500 mg of palladium / carbonate catalyst (10%) is added to the solution and the hydrogenation is preceded for 4 hours at normal pressure. After completion of the hydrogen incorporation, the catalyst is filtered off and extracted from the solvent.

Yield: 15.3 g

Melting point: 241-243C

Example 5a (2-methoxy-ethyl) -amide, pyridine-2,4-dicarboxylic acid 2-methyl ester (step 5)

4.8 ml of thionyl chloride were prepared in analogy to example 1 in the acid chloride and reacted with 5.7 ml of amide-forming 2-methoxyethylamine. The crude product is rubbed with diisopropyl ether and vacuum filtered.

Yield: 9.5 g Melting point: 74-76 ° C

Example 5b (3-methoxy-propyl) -amide, 2-methyl ester of pyridine-2,4-dicarboxylic acid (step 5)

Analogously to Example 5a, 3 g of the compound of Example 4 is converted into the acid chloride with 1.2 ml of thionyl chloride, and the reaction is reacted with 1.7 ml of amide-forming 3-methoxypropylamine . The crude product is chromatographed (ethyl acetate / methanol 15/1).

Yield: 2.6 g oil

Example 6a Pyridine-2,4-dicarboxylic acid 4- (2-methoxyethyl) amide (step 6) 2.3 g of sodium hydroxide (vanes) are dissolved in 70 ml of ethanol . At this temperature, a solution of 9 g of the compound of Example 5a in 30 ml of ethanol was added dropwise. After 4 hours, evaporation is continued until drying, extraction with little water and slow acidification with concentrated hydrochloric acid. The solution is evaporated and the product is recrystallized from hot ethanol.

Yield: 8 g

Melting point: 130-135 ° C

Example 6b Pyridine-2,4-dicarboxylic acid 4- (3-methoxypropyl) -amide (step 6)

The compound is prepared, analogously to example 6a from 3 g of the ester of example 5b. Yield: 2.6 g Melting point: 118-122 ° C 17

Claims (4)

A process for the preparation of 4-or 5-substituted pyridino-2-carboxylic acids of the formula I wherein R 1, R 2 and R 3 independently of one another represent hydrogen, C 1 -C 12 -alkyl, alkyl, 2- [2- (4-chlorophenyl) C 1 -C 4 -cycloalkyl condensed or non-fused with a benzene, aryl or heteroaryl ring, the radicals mentioned for R 2 - and R 3 are or are unsubstituted or substituted by one or several 3 radicals which are the same or different in which R3 represents halogen, hydroxy, cyano, nitro, nitroxy, amino, carboxyl, C1 -C4 -alkoxy, C1 -C4 -alkoxycarbonyl, C1 -C4 -alkylamino or C1 -C4 -alkylamino, arylamino, indolyl or phenyl, the indolyl radical and the phenyl radical being unsubstituted or substituted by 1, 2 or 3 times by halogen, nitro, C1 -C4 -alkyl or C1 -C4 -alkoxy, in the case of multiple substitutions, the radicals are the same or different or R4 and R4 are the same or different and represent hydrogen, C1 -C4 -alkyl, C1 -C4 -alkylcarbonyl or phenyl, or provided that R represents hydrogen, represents a -N (R4) (R3) radical, in which 18 R 2 R 1, provided that R represents hydrogen, represents a N-terminal linked radical of a Î ± -amino acid, a Î ± -amino acid alkyl ester, an amino acid amide, an alkylamide or dialkyl amide, the alkyl radicals having 1 to 4 carbon atoms and optionally being monosubstituted by phenyl and the C1-4 alkyl and C1-4 alkyl radicals may be branched or, provided that R represents hydrogen, represents a radical, attached through the N-terminus of a dispeptide or a tripeptide, the term "radical" in each case being understood to mean the corresponding Î ± -amino acid and its derivatives or the dipeptide or tripeptide, always bound by N terminal, and 21 has the meaning of R, the radicals R and R 2 being the same or different from each other, or R 2 and R 3 together with the nitrogen atom to which they are attached constitute a radical of formula II (CH2) n in which n is 1 to 3 and A is O, S, CH3 or -N (R3) -, wherein R4 is hydrogen, phenyl, C1-4 C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, these radicals being either unsubstituted or substituted by phenyl which in turn is unsubstituted or may be substituted one or more times by a halogen, nitro, cyano, carboxy, hydroxy, methyl, ethyl, methoxy ethoxy and trifluoromethyl, or -N (R), in which R4 represents hydrogen or C1-4 alkyl, C 1 -C 8 -alkyl, or -CONR 7 or -CON N (R 8) 9 or CONHR 6, wherein R 17 has the meaning of R or wherein g (R) 2 is a C 1 -C 8 -alkylene chain in which no Or a CH2 group not directly adjacent to the N atom is either O, S or N-R7, or where it represents C1 -C4 -alkoxycarbonyl or C1 -C7 -cycloalkyl, as well as their salts f is converted into the dihalide, - the dihalide is converted to the dibenzyl ester, the dibenzyl ester is selectively saponified in the 2-position, - the free acid function is converted into the monobenzyl ester, resulting in the corresponding acid chloride, and reacting the product c with an alcohol other than benzyl alcohol, with formation of the corresponding carboxylic acid 2-ester, the benzyl blocking group at the 4- or 5-position is hydrogenolytically separated and the resulting free acid at the 4 or 5-position is converted to the corresponding of acid and further characterized in that the acid chloride of the previous step is converted with an amine of the general formula III in which R 1 and R 2 have the meaning given in formula I, with the formation of the mixed pyridine-dicarboxylic acid compounds -4-amide-2-ester or pyridine-dicarboxylic acid-5-amide-2-ester and finally the said carboxylic acid 2-ester is converted into the free acid in the 2-position by reaction with a mineral acid. 2. A process according to claim 1, characterized in that 1 R 2 and R 2, independently of one another, represent C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -cycloalkyl, aryl or heteroaryl, wherein these radicals are defined as R 1 and R6 are unsubstituted or substituted, R 2 is halogen, hydroxy, cyano, amino, carboxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxycarbonyl, alkylamino or C1 -C4 -alkylamino, or phenyl, wherein the phenyl radical is either unsubstituted or mono- substituted by halogen, C1 -C2 -alkyl or C1 -C2 -alkoxy, or represents hydrogen, provided that R 2 is hydrogen or C 1 -C 4 -alkyl, or when R 2 represents hydrogen, represents a hydrogen atom or a hydrogen atom; radical bonded by the N-terminus of a -amino acid or of an alkyl ester of an amino acid, wherein the alkyl radical has 1 to 3 carbon atoms and is optionally monosubstituted by phenyl, and wherein the radical C alkyl may also be branched and has the meaning of R2 being the radicals R1 and R2 the same or different or 21 χρ. R1 and R3 > together with the nitrogen atom to which they are attached, form a radical of the formula II in which is 1 to 3 and 6 represents O, or -N (R °) -, in which represents hydrogen phenyl, C ^-C--alkyl, these radicals being unsubstituted or being substituted by C -C-C--alkoxycarbonyl or C -C-C--cycloalkyl as well as physiologically acceptable salts. -. R 1 and R 2 are each independently hydrogen, C 1 -C 4 -alkyl, in particular C 1 -C 4 -alkyl, C 1 -cycloalkyl, phenyl or pyridyl, wherein said radicals mentioned for R and D2 are either unsubstituted or substituted by one or two radicals in which R3 represents hydroxy, amino, carboxyl, C1 -C4 -alkoxy, especially methoxy, C1-4 alkoxycarbonyl or phenyl, wherein the phenyl radical is either unsubstituted or mono- or methoxy-substituted by methyl and methoxy and has the meaning of R3, the radicals R and R3 being the same or different from each other or R1-p2 and Λ together with the nitrogen atom to which they are attached form a radical of formula II (CH2) n (II) i η Α in which is 2 and represents O or Cl, as well as the physiologically acceptable salts. 4. A process for the preparation of compositions to influence the biosynthesis of collagen and collagen-like substances or the biosynthesis of Cl 2, characterized in that a compound of the formula I or a pharmaceutically acceptable salt thereof is incorporated in the composition as active ingredient. pharmaceutically acceptable salt, when prepared by a process according to any of the preceding claims, in an amount to obtain a content of the active substance in the composition up to 95%, preferably comprised between 10% and 75%, in combination with auxiliary and carrier substances pharmacological agents. of the 1990 application, under nos. The applicant claims German patent filed in 1 P 40 31 000.0 a prior to October 1, October 1, 1991. 23